Poly(ethylene glycol) (PEG) hydrogels have been extensively studied as synthetic matrices for the controlled release of therapeutics and as scaffolds for promoting tissue regeneration (1-3). The wide-spread use of PEG hydrogels in such applications is based on the hydrophilic, non-cytotoxic and non-immunogenic properties of PEG, effectively providing “stealth” capability to the biomaterial to mask the material from the host's immune system (4).
A significant drawback of PEG, however, is that the polymer lacks chemical versatility given that functionalization is typically limited to the hydroxyl chain end(s) (5). This limitation leads to synthetic challenges, which include synthesizing PEG-based hydrogels with desirable properties for various biomedical applications. PEG hydrogels are predominantly synthesized via step-growth polymerization of complimentary α,ω-functionalized PEG precursors (6) using thiolene chemistry (7) (including thiol-Michael addition (8), thiol-maleimide (9), and thiol-vinyl sulfone (10,11)), alkyne-azide click chemistry (6,12), Diels-Alder chemistry (13), oxime chemistry (14), or Schiff-base formation (15). Although step-growth polymerization minimizes network non-idealities, further chemistry is often required to improve the elasticity, injectability and degradability of these hydrogels to make them suitable for desired applications. In particular, given that only two cross-links can be formed by each functionalized PEG precursor (at chain ends), the resulting hydrogels are typically relatively weak or require high concentrations of PEG precursor. In addition, the lack of potential for direct chain functionalization introduces significant difficulties in terms of modifying the physical properties (e.g. acid or base responsiveness), the chemical reactivity (e.g. the introduction of orthogonally reactive functional groups) or the biological properties (e.g. via grafting of adhesive peptides or targeting ligands) of the hydrogels. As a result of these limitations, there is increasing interest in polymers with similar (biological) properties that can be synthesized in a facile manner with improved control over the polymer functionality (16).
Poly(oligoethylene glycol methacrylate) (POEGMA)-based polymers (17) have been proposed to meet this need. POEGMA can be synthesized by facile free radical copolymerization (18-20) and has been demonstrated to serve as an effective PEG analogue (21), exhibiting analogous non-immunogenic, non-cytotoxic and protein repellent properties to PEG (22). Furthermore, any acrylate or methacrylate-based functional monomer can easily be copolymerized with oligoethylene glycol methacrylate (OEGMA) to impart any desired functionality directly via copolymerization at the magnitude desired within the polymer chain. A number of POEGMA-based hydrogels have been reported to-date (23-27); however, with the exception of a 4-arm PEG-b-POEGMA polymer reported by Fechler et. al, which undergoes physical gelation at the physiological temperature of 37° C. (28), none of these hydrogels are either injectable or degradable in vivo, which severely limits their potential clinical application.
Gelation kinetics and the final morphology of the hydrogel are often linked, given that rapid cross-linking reactions can induce gelation faster than the timescale required for diffusional mixing of precursor polymers. As a result, depending on the type of mechanical mixing used during the gel formation process, regions of local heterogeneity may form within the polymer matrices of these gels that scatter light (significantly affecting the utility of these gels in ophthalmic applications (49)), alter the diffusional properties of small molecules through the gel, and/or degrade the mechanical properties of the gel.
Temperature-Responsive Hydrogels
Temperature-responsive hydrogels have attracted significant interest in the context of their capacity to macroscopically change their dimensions and, as a result, pore sizes (used, for example, for the triggered release of therapeutics). [51, 52] as well as their hydrophobicity (used, for example, for reversible cell adhesion/detachment)[53-55] as a function of temperature. The most widely reported of such materials is poly(N-isopropylacrylamide) (PNIPAM), which shows a lower critical solution temperature (LCST) in aqueous media just below physiological temperature. [56] However, concerns regarding the acute toxicity of the monomer N-isopropylacrylamide (NIPAM) as well as the chronic toxicity of degradation products of PNIPAM in vivo have hampered clinical use.[57,58] In addition, changing the LCST by copolymerization of more or less hydrophilic monomers often results in broadening of the phase transition that is typically undesirable in switchable materials. In contrast, POEGMA polymers can be synthesized through facile free radical polymerization to display an LCST in aqueous media that is governed by the ethylene oxide chain length (n) of the oligo(ethylene glycol) methacrylate (OEGMA) monomer.[59,60] Through the statistical copolymerization of diethylene glycol methacrylate (M(EO)2MA, n=2) and OEGMA475 (n=8,9),[61-63] hydrogels can be prepared that display a volume phase transition temperature (VPTT) ranging anywhere from ˜23° C. to ˜90° C. while maintaining comparatively sharp transitions [64-68].
pH-Responsive Hydrogels
pH-responsive hydrogels have attracted significant interest in the context of their capacity to sense (and actuate swelling changes) in different biological environments (e.g. lower pH values at infection or highly metabolically active sites such as tumors, protection of drugs in the acidic stomach environment and release where desired in the more basic intestine, etc.) In addition, the incorporation of charge inside hydrogels offers potential to significantly enhance the affinity of the hydrogel for charged bioactive agents (of the opposite charge to the charges in the hydrogel), improving their loading while slowing their release. In particular, amphoteric hydrogels that contain both positive and negative charged groups have attracted specific interest considering their charge distributions can mimic that of proteins; in this context, they have potential for controlled release of proteins without inducing protein denaturation as well as the potential to further reduce non-specific protein adsorption to materials (as demonstrated for a variety of zwitterionic materials such as poly(betaines)).